Keap1‑Nrf2‑ARE
One of the most essential defense systems against oxidative and/or electrophilic stressors is the Keap1–Nrf2–ARE Kelch-like ECH-Associating protein 1 nuclearfactor erythroid 2 related factor 2-antioxidant response element, which is linked to inflammatory disorders. In response to ROS exposure, it activates a cytoprotective mechanism. The Nrf2-ARE transcriptional pathway regulates genes that encode proteins involved in the detoxification and elimination of reactive oxygen species (ROS) and electrophiles (Nguyen, Nioi & Pickett, 2009). The Keap1–Nrf2–ARE pathway is important for cell protection against oxidative and electrophilic stress. The ability of Nrf2–ARE activators to boost a battery of critical cell-protective genes involved in reducing oxidative damage and inflammation may be exploited in the development of antioxidant, anti-inflammatory, and anticancer medicines (Lu, Ji, Jiang & You, 2016). The study of (Shang et al., 2013) achieved two goals. It first identified the timing of Keap1 inhibition and Nrf2 activation in rats during the early stages of ICH. Nrf2 is an important endogenous regulator of cellular oxidative stress resistance. Intravenous treatment of a Nrf2 activator (BARD) significantly raised Nrf2 and HO-1 expression earlier, thereby protecting neurons from IRI. Taken together, their findings revealed that Nrf2 activators may be neuroprotective in patients with IRI (Takagi et al., 2014). In the (Zhao et al., 2007) study, activation of Nrf2 by SF was related with enhanced expression of many antioxidative enzymes known to play essential roles in oxidative stress defense, including catalase, SOD, NAD(P)H dehydrogenase, quinone-1, and glutathione S-transferase. Nrf2 deficiency contributes to ROS-induced DNA damage and death largely in neurons in the early stages of ICH, according to (Wang et al., 2007) Activating Nrf2 prevents leukocytes from entering the injury site and preventing excessive free radical damage to the brain tissue. Despite the fact that more research with selective Nrf2 inducers and inhibitors is needed, the data suggest that Nrf2 could be a therapeutic target for the treatment of ICH. (Zhang et al., 2019) found that MitoQ promotes mitophagy and reduces mitochondrial oxidative stress-related neuronal apoptosis in EBI after SAH via the Keap1/Nrf2/PHB2 pathway, which is linked to improved short- and long-term neurological impairment. MitoQ could thus be used as an antioxidant therapy for EBI as well as a treatment for delayed neurological impairments following SAH. SalA (10 and 50 mg/kg/day) administered intraperitoneally was shown to protect EBI following SAH, at least in part due to its antioxidative, anti-inflammatory, and antiapoptotic properties. The following is the evidence that led to this conclusion: At 48 hours following a SAH in a rat model, SalA dramatically alleviated neurological impairments, reduced brain edema and BBB permeability, decreased inflammation factors, and repressed oxidative stress and cortical neuron death. Furthermore, SalA reduced MDA and ROS production produced by SAH while increasing GSH concentration and GSH-Px activity. These findings suggested that treating rats with SalA would be an effective way to protect their brains from EBI after SAH (Gu et al., 2017). SAH treatment may one day be based on this promising new discovery, but further studies are needed to confirm it.